CN1688587A - Process and intermediates for the preparation of the thienopyrrole derivatives - Google Patents

Process and intermediates for the preparation of the thienopyrrole derivatives Download PDF

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CN1688587A
CN1688587A CNA038236176A CN03823617A CN1688587A CN 1688587 A CN1688587 A CN 1688587A CN A038236176 A CNA038236176 A CN A038236176A CN 03823617 A CN03823617 A CN 03823617A CN 1688587 A CN1688587 A CN 1688587A
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alkyl
amino
group
sulfamyl
formamyl
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CN100378106C (en
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P·M·墨累
J·S·帕克
P·肖菲尔德
A·斯托克
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AstraZeneca AB
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30Hetero atoms other than halogen
    • C07D333/36Nitrogen atoms
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

A process for preparing a compound of formula (I) where R<4> and R<5 >are as defined in the specification; and R<6> is hydrogen or a protecting group, which process comprises cyclisation of a compound of formula (II) where R<4>, R<5>and R<6> are as defined in relation to formula (I) and R<7>is a nitrogen-protecting group, and removing protecting group R<7>-, and thereafter if desired or necessary, removing any protecting group R<6> to obtain the corresponding carboxylic acid. Novel intermediates and the use of the products in the preparation of pharmaceutical compounds is also described and claimed.

Description

The preparation method of Thienopyrroles derivative and intermediate
The present invention relates to a kind of preparation method of new intermediate, wherein this intermediate is used for preparation treatment compounds effective, and the new intermediate that uses in the method.
Having the active compound of glycogen phosphorylase is described among the WO 02/20530.These compounds have a kind of general formula suc as formula (A) expression
Wherein X, Y and Z especially are selected from-CR 4=CR 5-S-, R 4And R 5Be independently selected from hydrogen, halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, C 1-6Alkyl S (O) aWherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino and C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino; N is 0-4, and R 1, R 2And R 3It is specified organic group.
The acid of the general through type of these compounds (B)
Be prepared with suitable amine reaction.The acid group of formula (B) is prepared according to following flow process:
Figure A0382361700081
But this method is difficult to realize, because it may set off an explosion.
The applicant has found a kind of improving one's methods of some intermediate that prepare.
The invention provides the method for a kind of preparation formula (I) compound.
R wherein 4And R 5Be independently selected from hydrogen, halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, C 1-6Alkyl S (O) aWherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino and C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino; And R 6Be hydrogen or a kind of protecting group, this method comprises: with formula (II) compound Cheng Huan
R wherein 4, R 5And R 6Suc as formula definition in (1), R 7Be a kind of nitrogen-protecting group, then remove protecting group R 7, after this if desired or necessary, remove any protecting group R 6, obtain corresponding carboxylic acid.
Cheng Huan suitably at organic solvent for example in methyl alcohol or the dimethyl formamide (DMF), carry out in the presence of alkali.Suitable alkali particularly comprises for example alkali metal alcoholate of highly basic, and for example sodium methylate still also can comprise weak base for example alkaline carbonate such as salt of wormwood.This reaction is carried out in a wide temperature range suitably, for example in the temperature range of envrionment temperature to 70 ℃, and carries out under the reflux temperature of solvent easily.Under these conditions, in identical reactions steps, remove R usually 7But, depend on the character of the group that uses, might in step subsequently, remove R 7, for example remove R by acid or macromolecule alkali for hydrolysis 7
Can use ordinary method to carry out acid hydrolytic reaction, particularly use acid for example trifluoromethanesulfonic acid, acetate or hydrochloric acid.Macromolecule alkali for hydrolysis is for example carried out in the presence of the alkali metal hydroxide at alkali suitably, particularly carries out in the presence of sodium hydroxide or potassium hydroxide.
Protecting group R 7Suitable example be listed in T.W.Green, Protecting Groups inOrganic Synthesis, J.Wiley and Sons in 1991, particularly is called as those of nitrogen-protecting group.
Protecting group R 7Object lesson be the group of minor (i) expression
Figure A0382361700091
R wherein 8Be alkyl or heterocyclic radical, these two kinds of groups can be chosen wantonly and be substituted.
As used herein, wording " alkyl " comprises any structure that comprises carbon and hydrogen atom.For example, these can be for example for example benzyl or cycloalkyl, cycloalkenyl group or cycloalkynyl radicals of phenyl or naphthyl, aralkyl of alkyl, alkenyl, alkynyl, aryl.Suitable alkyl contains up to 20 carbon atoms, preferably contains up to 10 carbon atoms.
Term " aryl " is meant for example phenyl or naphthyl of aromatic ring.
Term " heterocycle " comprises aromatic ring or non-aromatic ring, for example contains 4-20,5-8 annular atoms suitably, and wherein at least one, 1-4 wherein is individual suitably is for example oxygen, sulphur or nitrogen of heteroatoms.They can be monocycle or condensed ring, for example dicyclo or three-ring system.The example of these groups comprises furyl, thienyl, pyrryl, pyrrolidyl, imidazolyl, triazolyl, thiazolyl, tetrazyl, oxazolyl, isoxazolyl, piperidyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
Term " heteroaryl " is meant and comes down to aromatic heterocyclic group.Therefore, these can comprise one or more carbon atoms displaced ring-type aromatic hydrocarbon of heteroatoms.If described heteroaryl contains unnecessary 1 heteroatoms, this heteroatoms can be identical or different.The example of heteroaryl comprises pyridyl, pyrimidyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrryl, pyranyl, isobenzofuran-base, chromenyl, xanthenyl, indyl, pseudoindoyl, indolizine base, triazolyl, pyridazinyl, indazolyl, purine radicals, quinolizinyl, isoquinolyl, quinolyl phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl and benzo [b] thienyl.Preferred heteroaryl is 5 yuan or 6 yuan of rings, and contains one to three heteroatoms.
Heterocycle and hydrocarbyl group R 8Suitable optional substituting group comprise nitro, cyano group, halogen, oxo ,=CR 13R 14, C (O) xR 12, OR 12, S (O) yR 12, NR 13R 14, C (O) NR 13R 14, OC (O) NR 13R 14,=NOR 12,-NR 12C (O) xR 13,-NR 12CONR 13R 14,-N=CR 13R 14, S (O) yNR 13R 14Or NR 12S (O) yR 13, R wherein 12, R 13And R 14Be independently selected from hydrogen or the optional alkyl that replaces, perhaps R 13And R 14Form optional replace an and optional for example S (O) of other heteroatoms that contains together y, oxygen and nitrogen ring, x is 1 or 2 integer, y is 0 or the integer of 1-3.Hydrocarbyl group R 8Also can comprise heterocyclic substituent, itself can choose wantonly by listed optional substituting groups above one or more and replace.Heterocyclic group also can be replaced by hydrocarbyl group, and described hydrocarbyl group also can be chosen wantonly by listed group above any and replace.
Preferably, R 8Be for example alkyl, aryl or aralkyl of a kind of hydrocarbyl group.Most preferably, R 8Be the straight chained alkyl of 1-6 carbon atom, particularly straight chain C 1-4Alkyl, for example methyl.
Radicals R 4And R 5Object lesson be hydrogen, halogen, nitro, cyano group, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, formamyl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl and C 1-6Alkanoyloxy.
Aptly, R 4And R 5Be independently selected from hydrogen, halogen, nitro, cyano group, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, formamyl, sulfamyl, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl, C 1-4Alkoxyl group, C 1-4Alkyloyl and C 1-4Alkanoyloxy.
Preferably, R 4And R 5Be independently selected from hydrogen and halogen for example chlorine, fluorine and bromine, particularly chlorine.
Most preferably, R 4Be hydrogen, R 5Be for example chlorine of halogen.
Protecting group R 6Object lesson be any organic group that can remove by hydrogenation or hydrolysis.These groups comprise optional alkyl that replaces or the optional heterocyclic radical that replaces.These groups can be with top listed about R 7Those are similar.
Protecting group R 6Suitable example be listed in T.W.Green, Protecting Groups inOrganic Synthesis, J.Wiley and Sons in 1991, particularly is called as those of sour protecting group.
Especially, R 6Be a kind of alkyl, for example C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, aryl be phenyl or aralkyl benzyl for example for example.
Protecting group R 6Change into hydrogen and use ordinary method to carry out suitably, for example the method described in WO02/20530.Especially, at organic solvent for example in the methyl alcohol, under 20-80 ℃, and easily under the reflux temperature of described solvent, react described compound and alkali for example lithium hydroxide react.
The compound of formula (II) is the compound of through type (III) aptly
R wherein 4And R 5Suc as formula in (I) define R 6And R 7Suc as formula defining in (II), and the compound of formula (IV):
LCH 2COOR 6
(IV)
Wherein L is a for example halogen bromine particularly of a kind of leavings group, reacts and prepares.This reaction in the presence of alkali, is for example carried out in dimethyl formamide, N-Methyl pyrrolidone (NMP) or the acetone at organic solvent aptly.Suitable alkali comprises alkaline carbonate, supercarbonate, oxyhydroxide or methylate, but for example alkaline carbonate or supercarbonate, for example saleratus of weak base preferably.This reaction can at high temperature be carried out, and for example according to employed solvent, can carry out under 30-100 ℃ temperature.For example when dimethyl formamide was solvent, this reaction was preferably carried out under 50-70 ℃ temperature, most preferably carries out under about 60 ℃ temperature.For example when NMP is solvent, this is reflected under 30-50 ℃ the temperature and carries out, and preferably carries out under about 40 ℃ temperature.
The compound by formula V aptly of formula (III)
Figure A0382361700121
R wherein 4And R 5As shown in top formula (I), R 7As shown in top formula (II), formylation be prepared, this reaction can use ordinary method for example to carry out the Vilsmeier-Haack reaction.In this reaction, the compound of formula V with contain for example compound of formula (VI) of formyl radical reagent
R wherein 9And R 10Be independently selected from phenyl and alkyl (the particularly low alkyl group of 1-4 carbon atom, for example methyl), in the presence of phosphorus oxychloride, react.This reaction under moderate temperature, is at room temperature carried out aptly easily.The compound of formula (VI) also can be used as a kind of solvent, and wherein for example it is DMF, perhaps can use a kind of different organic solvent, for example methylene dichloride.
Yet the applicant finds that under certain conditions, this reaction generates the amidine of the formula (VII) of significant proportion
Figure A0382361700123
R wherein 4And R 5Suc as formula (I) define R 9And R 10Define suc as formula (VI).Under acidic conditions, for example containing organic acid for example in the solvent of acetate, by with the compound reaction of formula (VIII), the compound of formula (VII) can change the compound of an accepted way of doing sth (III)
(R 7) 2O
(VIII)
R wherein 7Suc as formula defining in (II).For example 80-150 ℃ temperature of high temperature is used in this reaction, preferably uses 110-130 ℃ temperature.Easily, this reaction can be carried out under the reflux temperature of described solvent.The object lesson of formula (VIII) compound is those, wherein radicals R 7Be the group of minor (i) as defined above, R wherein particularly 8Be those of methyl, the compound of this pattern (VIII) is a diacetyl oxide.
Usually, when the containing the formylation compound and use solvent for example methylene dichloride reacts of the compound of formula V and formula (VI), the quantity of the formula of generation (VII) amidine is not remarkable, on the contrary, obtains the required compound of the formula (III) of good yield.
The compound of formula V is the compound of through type (IX) aptly
R wherein 4And R 5Suc as formula (I) define R 11O (C=O) is a kind of unsettled nitrogen-protecting group, with formula (VIII) compound as defined above under acidic conditions, for example for example react in the solvent of acetate containing organic acid.For example 80-150 ℃ temperature of high temperature is used in this reaction, preferably uses 110-130 ℃ temperature.Easily, this reaction can be carried out under the reflux temperature of described solvent.
R 11The suitable unstable nitrogen-protecting group of O (C=O) comprises tert-butoxycarbonyl or carbobenzoxy-(Cbz).
The compound of formula (IX) or known (for example referring to people such as Binder, Synthesis, (1977, (4) 255-6) or can prepare by known compound.Especially, the compound of formula (IX) is aptly by the compound with formula (X)
R wherein 4And R 5Suc as formula defining in (I), at formula R 11Carry out the Curtius rearrangement reaction under the alcohol of OH exists and prepare.In this reaction, the compound of formula (X) and diphenyl phosphoryl azide reaction are converted into the carbonyl azide thing with acidic group, and it becomes acid amides by the isocyanic ester thermolysis.Proper reaction conditions is described below.
Formula (II), (III) and compound (VII) are new, and constitute another aspect of the present invention.
Formula (IV), (V), (VI), (VIII), (IX) and compound (X) are compound known, and perhaps they can be prepared by ordinary method by known compound.
The compound of formula (I) uses in preparation of pharmaceutical compounds aptly, particularly has the active compound of glycogen phosphorylase, described in WO 02/20530 and EP-A-1088824.
Therefore, on the other hand, the invention provides a kind of aforesaid method, be used for the compound of preparation formula (I), wherein R 6Be hydrogen, comprise that further the compound of resulting formula (I) and the amine of formula (XI) react,
Figure A0382361700141
R wherein 14Be selected from hydrogen or C 1-8Alkyl,
M is the integer of 0-4,
Each R 15Be identical or different, and be selected from hydrogen, halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl, C 3-8Cycloalkyl C 1-6Alkyl, aryl, aryl C 1-6Alkyl, heterocyclic radical and (heterocyclic radical) C 1-6Alkyl; R wherein 15On carbon, can choose wantonly by the group of one or more P of being selected from and replace, and if wherein described heterocyclic radical contain one-NH-part, nitrogen can be chosen wantonly by a group that is selected from R and replace so;
Each R 16Be identical or different and be selected from hydrogen and C 1-6Alkyl;
R 17Be selected from hydrogen, halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-4Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, sulfamyl amino, N-(C 1-6Alkyl) sulfamyl amino, N, N-(C 1-6Alkyl) 2Sulfamyl amino, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulfonyl-amino carbonyl, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino and group-E-F-G-H;
Wherein E and G be independently selected from direct key ,-O-,-S-,-SO-,-SO 2-,-OC (O)-,-C (O) O-,-C (O)-,-NR a,-NR aC (O)-,-C (O) NR a,-SO 2NR a-,-NR aSO 2-,-NR aC (O) NR b-,-OC (O) NR a-,-NR aC (O) O-,-NR a-SO 2NR b-,-SO 2NR aC (O)-and-C (O) NR aSO 2-; R wherein aAnd R bSelect hydrogen and the optional C that is replaced by group V independently 1-6Alkyl;
F is the optional C that is replaced by one or more Q 1-6Alkylidene group or direct key;
H is selected from aryl, C 3-8Cycloalkyl and heterocyclic radical; Wherein H can choose wantonly on carbon by the group of one or more S of being selected from and replace, if wherein described heterocyclic radical contains one-NH-part, nitrogen can be chosen wantonly by a group that is selected from T and replace so;
P, S and Q are independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl, aryl and heterocyclic radical; Wherein P, S and Q can be randomly on carbon and are replaced by one or more groups that are selected from V independently, and if described heterocyclic radical contain one-NH-part, nitrogen can be chosen wantonly by a group that is selected from U and replace so;
V is selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino-, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, kharophen, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl-N-ethyl sulfamyl, morpholino, morpholino carbonyl, N-benzylamino formyl radical and 4-hydroxy piperidine subbase carbonyl;
R, T and U are independently selected from C 1-4Alkyl, C 1-4Alkyloyl, C 1-4Alkyl sulphonyl, C 1-4Alkoxy carbonyl, formamyl, N-(C 1-4Alkyl) formamyl, N, N-(C 1-4Alkyl) formamyl, phenyl, benzyl, carbobenzoxy-(Cbz), benzoyl and benzenesulfonyl, wherein R, T and U can randomly and independently be replaced by one or more groups that are selected from V on carbon;
Compound with production (XII)
R wherein 4, R 5, R 15, R 16, R 17With m as defined above, or hydrolyzable ester in its pharmacy acceptable salt or the body.
The object lesson of formula (XII) compound is the compound described in WO 02/20530, wherein R 14Be hydrogen.For example, the suitable combination thing of formula (XII) is a compound, wherein R 4And R 5As defined above, R 14Be hydrogen, m is 0 and R 17Be group-E-F-G-H;
Wherein E, F and G each be a direct key;
H is C 3-12Cycloalkyl; its optional with one benzo-fused; wherein H can be replaced by one or more group S on carbon, and wherein S is independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl, aryl and heterocyclic radical; Wherein S can randomly and independently be replaced by one or more groups that are selected from V on carbon;
V is selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino-, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, kharophen, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl-N-ethyl sulfamyl, morpholino, morpholino carbonyl, N-benzylamino formyl radical and 4-hydroxy piperidine subbase carbonyl;
Or its pharmacy acceptable salt.
The compound of other suitable formula (XII) is a compound, wherein R 4And R 5As defined above, R 14Be hydrogen, m is 0 and R 17Be group-E-F-G-H;
Wherein E, F and G each be a direct key; And
H is the cyclic amide of following formula
Wherein tie point is the carbon atom adjacent with carbonyl, k is 0,1 or 2, l is 0,1 or 2, (k+l) is 1,2 or 3 like this, carbon atom among one of them k or the l can be by sulfur, and wherein H is optional on the carbon atom adjacent with aromatic ring is replaced by a group that is selected from S, and can choose wantonly independently by a group that is selected from T on nitrogen-atoms and replace;
S is selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl, aryl and heterocyclic radical; Wherein S can be randomly on carbon and is replaced by one or more groups that are selected from V independently, and if wherein described heterocyclic radical contain one-NH-part, nitrogen can be chosen wantonly by a group that is selected from U and replace so;
T and U are independently selected from C 1-4Alkyl, C 1-4Alkyloyl, C 1-4Alkyl sulphonyl, C 1-4Carbalkoxy, formamyl, N-(C 1-4Alkyl) formamyl, N, N-(C 1-4Alkyl) formamyl, phenyl, benzyl, carbobenzoxy-(Cbz), benzoyl and benzenesulfonyl, wherein R, T and U can randomly and independently be replaced by one or more groups that are selected from V on carbon;
V is selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino-, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, kharophen, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl-N-ethyl sulfamyl, morpholino, morpholino carbonyl, N-benzylamino formyl radical and 4-hydroxy piperidine subbase carbonyl;
Or hydrolyzable ester in its pharmacy acceptable salt or the body.
Other example of formula (XII) compound is a compound, wherein R 14Be hydrogen, R wherein 4And R 5Be independently selected from hydrogen, halogen or C 1-6Alkyl,
M is 1; R 15Be hydrogen or aryl C 1-6Alkyl, R 16Be hydrogen or C 1-6Alkyl, and R 17Be selected from group-E-F-G-H; Wherein E, F and G each be direct key;
H is a kind of undersaturated 5 yuan of heterocyclic groups; it contains at least one nitrogen-atoms and one or two is selected from the annular atoms of oxygen and sulphur; and wherein H can choose wantonly on carbon by one or more group S and replace, and wherein S is independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl and aryl;
Or its pharmacy acceptable salt.
Other object lesson of formula (XII) compound is a compound, wherein R 14Be hydrogen, R 4And R 5Be independently selected from hydrogen, halogen or C 1-6Alkyl,
M is 1; And R 17Be group-E-F-G-H;
Wherein E is direct key;
F is a methylene radical;
Wherein G is-C (O) NR a-, R wherein aBe selected from hydrogen or the optional C that is replaced by group V 1-6Alkyl;
H is an aryl, and it can be chosen wantonly on carbon by the group of one or more S of being selected from and replace;
S is selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl, aryl and heterocyclic radical; Wherein S can randomly and independently be replaced by one or more groups that are selected from V on carbon;
V is selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino-, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, kharophen, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl-N-ethyl sulfamyl, morpholino, morpholino carbonyl, N-benzylamino formyl radical and 4-hydroxy piperidine subbase carbonyl;
Or its pharmacy acceptable salt.
Other particular compound of formula (XII) is a compound, wherein group
Figure A0382361700191
It is minor group (ii)
R wherein 14As defined above, R 18Be aryl, substituted aryl, heteroaryl or substituted heteroaryl, R 19Be a key or group-CH (OH)-, and R 20Be group-C (=O)-A or group-CH (OH)-C (=O)-A, wherein A is NR dR d,-NR aCH 2CH 2OR aOr
Figure A0382361700202
Or
Figure A0382361700203
Each R aAnd R bBe independently hydrogen or-C 1-C 8Alkyl;
Each R dBe hydrogen, C independently 1-8Alkyl, C 1-C 8Alkoxyl group, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
Each R cBe independently hydrogen ,-C (=O) OR a,-OR a,-SR aOr-NR aR aAnd each n is 1-3 independently, and
X 1Be NR a,-CH 2-, O or S.
Aryl and heteroaryl Q and R dSubstituent example comprise halogen, C 1-8Alkoxyl group, C 1-8Alkyl, trifluoromethyl, amino, list-or two-(C 1-8Alkyl) amino, nitro, cyano group, carboxyl or its C 1-8Alkyl ester.
To specifically describe the present invention by embodiment below, wherein, except as otherwise noted:
(i) temperature with centigradetemperature (℃) expression; Under room temperature or envrionment temperature, carry out, that is, in 18-25 ℃ temperature range, carry out, and for example carry out under the argon atmospher at the rare gas element atmosphere;
(ii) organic solution is dry in anhydrous magnesium sulfate; Rotary Evaporators (600-4000 pascal is under reduced pressure used in the evaporation of solvent; 4.5-30mmHg) and carry out being no more than under 60 ℃ the bath temperature;
(iii) chromatography is meant the flash chromatography on silica gel method; Thin layer chromatography (TLC) carries out on silica-gel plate;
(iv) common, reaction process is monitored with TLC, and the given reaction times only is illustrative;
(v) yield when providing, only is illustrative, those that not necessarily can be by making great efforts that process exploitation obtains; More if desired material can repeat preparation;
(vi) when providing, the NMR data provide with the form of the δ value of principal character proton, and with PPM (ppm) expression, tetramethylsilane (TMS) uses perdeuterated dimethyl sulfoxide (DMSO) (DMSO-d as interior mark under 300MHz 6) as solvent or use other solvent (shown in this article time) to comprise deuterate chloroform CDCl 3Measure;
(vii) chemical symbol has their common implications; Use SI units and symbol;
(absolute pressure of representing with pascal (Pa) that viii) reduces pressure provides; The gauge pressure that the high pressure Israel and Palestine are represented provides;
(ix) solvent ratio provides with volume ratio: volume (v/v) symbol;
(x) mass spectrum (MS) moves under 70 electron-volts electronic energy, in chemi-ionization (CI) mode, uses a probe that directly exposes; Wherein said ionization is subjected to electronic impact (EI), fast atom bombardment(FAB) (FAB) or electrospray (ESP) effect; Wherein mostly just with ionic form report, it is meant the parent quality to the m/z value, and except as otherwise noted, the value that is marked is (M-H) -
Use following abbreviation:
The DMSO=methyl-sulphoxide
The DCM=methylene dichloride
THF is a tetrahydrofuran (THF)
HPLC is a high pressure liquid chromatography
DMF is a dimethyl formamide
THF is a tetrahydrofuran (THF)
LCMS is a liquid chromatography/mass spectrometry
Embodiment 1
Step 1
Figure A0382361700211
In argon atmospher, 5-chlorothiophene-2-carboxylic acid (5.48g) is dissolved in the dry trimethyl carbinol (34ml) of heat, add triethylamine (4.7ml), then add diphenyl phosphoryl azide (DPPA) (7.26ml).Then, mixture slowly is heated to backflow, and refluxed about 12 hours.
Then, reaction mixture is poured into H 2O (~180ml).Filter the black suspension of gained, solid H 2The O washing is dried to brown powder under the suction then.This brown powder is dissolved in the ether, and gained solution is at MgSO 4In dry, filter, evaporation obtains required product, (5-chloro-2-thienyl) t-butyl carbamate is a kind of dun solid (yield=6.75g). 1H?NMR(400MHz,d 6-DMSO)6.82(d,1H),6.34(d,1H),1.50(s,9H)
Step 2
The mixture of diacetyl oxide (6.42ml) in acetate (60ml) joined in the product (7.48g) of step 1, the gained mixture heated 4 hours down at 120 ℃.After the reaction mixture cooling, be poured in the water, and extract with EtOAc.The saturated K of EtOAc layer 2CO 3Solution washing is at Na 2SO 4Middle dry, filter, vapourisation under reduced pressure obtains a kind of black solid.Carry out silica gel chromatography and separate, use CH 2Cl 2To Et 2The elutriant of O obtains N-(5-chloro-2-thienyl) ethanamide (4.63g, 83%), is a kind of light brown solid. 1H?NMR(400MHz,d 6-DMSO)11.33(br?s,1H),6.82(d,1H),6.40(d,1H),2.05(s,3H);ESP -174.29
Step 3
The product (1.09g) of step 2 is dissolved in dimethyl formamide (DMF) (3ml), and in ice bath, cools off.Drip POCl 3(0.58ml), dark-coloured mixture stirred 30 minutes at 0 ℃, was warmed to room temperature then, then at room temperature stirred 64 hours.
Reaction mixture is poured in the frozen water, and water is extracted in the methylene dichloride.Dichloromethane layer is at MgSO 4Middle dry, to filter, evaporation obtains a kind of black glue.Purify with suction silicon-dioxide column chromatography, bring into use hexane, then in the vertical material of post, add CH as elutriant 2Cl 2Increase the concentration (10% one-level) of ether lentamente, up to becoming pure ether.With the some fractions of lcms analysis.Merge (MH)+be 217 and (MH) -Be 2 fractions of 202.They are evaporated, obtain a kind of yellow solid (0.53g).LCMS and 1H NMR spectroscopic analysis shows that this is a kind of required N-(5-chloro-3-formyl radical-2-thienyl) ethanamide (87%) and N '-(5-chloro-3-formyl radical-2-thienyl)-N, the mixture of N-dimethylimino methane amide (13%).
Figure A0382361700231
1H NMR N-(5-chloro-3-formyl radical-2-thienyl) ethanamide (300MHz, d 6-DMSO) 11.65 (br s, 1H), 9.93 (s, 1H), 7.22 (s, 1H), 2.25 (s, 3H); ESP -202.21;
N '-(5-chloro-3-formyl radical-2-thienyl)-N, N-dimethylimino methane amide (300MHz, d 6-DMSO) 9.90 (s, 1H), 7.97 (s, 1H), 6.93 (s, 1H), 3.13 (s, 3H), 3.02 (s, 3H); ESP +217.22
Step 4
The mixture (0.53g) of step 3 is dissolved in the acetate (5ml),, then adds H to wherein adding diacetyl oxide (0.5ml) 2O (0.25ml).Mixture heating up was refluxed about 1 hour, and the tlc analysis revealed does not have dimethylamidine derivative residue.
Reaction mixture is poured into H 2Among the O, filtering-depositing.Water is extracted in the methylene dichloride and 19: 1 mixture of methyl alcohol, precipitation is dissolved in a kind of similar mixture.The organic solution that merges with salt of wormwood dilute aqueous soln washing, about 12 to guarantee pH, then at MgSO 4Middle dry.Filter, vapourisation under reduced pressure obtains required product, and N-(5-chloro-3-formyl radical-2-thienyl) ethanamide is a kind of yellow, an orange solids (yield=0.53g). 1H?NMR(300MHz,d6-DMSO)11.65(br?s,1H),9.93(s,1H),7.22(s,1H),2.25(s,3H);ESP -202.21
Alternative step 3 (does not need step 4)
Figure A0382361700241
Methylene dichloride (7ml), POCl 3(2.24ml) and DMF (3.10ml) at room temperature stirred 15 minutes, form a kind of clear solution.The product (3.50g) of step 2 is dissolved in the methylene dichloride (70ml), in 1.5 hours, joins POCl by syringe pump 3In/DMF the solution, generate a kind of dark solution.Reaction was at room temperature stirred 23 hours.Add saturated sodium bicarbonate (200ml) to reaction mixture gradually, reach till 8 up to pH.Separate organic phase, in ice bath, (1M, 150ml and 2M 100ml), reach till 14 up to pH to add sodium hydroxide in solution lentamente.Combining water layer, (2M 150ml), reaches till 3 up to pH to add hydrochloric acid.Product is extracted in the ethyl acetate (150ml), then with salt solution (25ml) washing.Evaporating solvent obtains N-(5-chloro-3-formyl radical-2-thienyl) ethanamide (2.09g, 52%), is a kind of lead solid. 1H?NMR(400MHz,CDCl 3)11.37(br?s,1H),9.69(s,1H),7.01(s,1H),2.31(s,1H)
Step 5
In argon gas, the product (460mg) of step 4 is placed in the dry glass vessel, and is dissolved among the dry DMF (2ml).In this solution, add saleratus (567mg), then add methyl bromoacetate (0.54ml).Mixture heating up to 40 ℃, and heating 150 minutes under this temperature, then under 60 ℃ heating 120 minutes.Reaction is at room temperature stirred and is spent the night, and second day, heats 270 minutes down at 60 ℃ again.
Product is distributed between methylene dichloride and water, and dichloromethane layer is at MgSO 4Middle dry, filter, vapourisation under reduced pressure obtains a kind of dark-coloured oil.Purify with suction silicon-dioxide column chromatography, bring into use hexane, then in the vertical material of post, add CH as elutriant 2Cl 2With CH 2Cl 2Concentration increase (10% increment, 50ml fraction) to 100%CH 2Cl 2, at CH 2Cl 2The time keep some fractions, increase Et then 2The concentration of O (1% increment) is till removing deblurring from pillar.The spot that collection is equivalent to required N-ethanoyl-N-(5-chloro-3-formyl radical-2-thienyl) methyl aminoacetate (using LCMS to identify) uses in step subsequently.
1H?NMR(300MHz,d-DMSO)9.93(s,1H),7.20(s,1H),4.40(br?s,2H),3.77(s,3H),2.06(s,3H).
Alternative step 5
In argon gas, the product (1.50g) of step 4 is placed in the dry glass vessel, and is dissolved among the dry NMP (10ml).In solution, add saleratus (2.96g), then add NMP (5ml), methyl bromoacetate (2.79ml) and t-butyl methyl ether (0.5ml).With mixture heating up to 40 ℃, and heating 23 hours under this temperature.Product is distributed between EtOAc and water, and the EtOAc layer is at MgSO 4Middle dry, filter, vapourisation under reduced pressure obtains a kind of orange oil.Purify with suction silicon-dioxide column chromatography, bring into use CH 2Cl 2As elutriant, then in the vertical material of post, add CH 2Cl 2Increase Et 2The concentration of O (0.25% increment) after the evaporation, obtains product N-ethanoyl-N-(5-chloro-3-formyl radical-2-thienyl) methyl aminoacetate (1.20g, 59%), and product is a kind of clarifying yellow glue. 1H?NMR(300MHz,d 6-DMSC)9.93(s,1H),7.20(s,1H),4.40(br?s,2H),3.77(s,3H),2.06(s,3H)
Step 6
Figure A0382361700252
Under argon atmospher, the product (170mg) of step 5 is dissolved among the MeOH, add the solution (0.62ml, 25% solution) of sodium methylate in methyl alcohol, cause the color of solution slightly to deepen, generate a kind of brown clear solution.Mixture was refluxed 1 hour.
Reaction mixture is distributed between methylene dichloride and water, at MgSO 4Middle dry methylene chloride layer filters and vapourisation under reduced pressure, obtains required product, 2-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylate methyl ester, and product is a kind of yellow solid (yield=97mg (93%).The structure of product by LCMS and 1The H NMR (Nuclear Magnetic Resonance) spectrum confirms. 1H?NMR(300MHz,d 6-DMSO)9.40(br?s,1H),6.91(s,1H),6.82(s,1H),3.82(s,3H);ESP -214.16
Alternative step 6
Figure A0382361700261
The product (1.20g) of step 5 is dissolved among the DMF (15ml), adds K 2CO 3(631mg), then with mixture heating up to 60 ℃, and heating 90 minutes under this temperature.After mixture is cooled to room temperature, be poured in the water (30ml), the filtration white solid also washes with water, obtains required product, 2-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylate methyl ester (741mg, 79%), and product is a kind of linen solid. 1H?NMR(300MHz,d 6-DMSO)9.40(br?s,1H),6.91(s,1H),6.82(s,1H),3.82(s,3H);ESP -214.16。

Claims (11)

1. the method for a preparation formula (I) compound.
Figure A038236170002C1
R wherein 4And R 5Be independently selected from hydrogen, halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino and C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino; And R 6Be hydrogen or a kind of protecting group, this method comprises: with formula (II) compound Cheng Huan
R wherein 4, R 5And R 6Suc as formula definition in (1), R 7Be a kind of nitrogen-protecting group, then remove protecting group R 7, after this if desired or necessary, remove any protecting group R 6, obtain corresponding carboxylic acid.
2. the process of claim 1 wherein protecting group R 7During the reactions steps identical, be removed with becoming ring.
3. claim 1 or 2 method, wherein in the structure of formula (II), R 7It is the group of a minor (i)
R wherein 8It is the straight chained alkyl of 1-6 carbon atom.
4. the method for each claim of front, wherein R 4And R 5Be independently selected from hydrogen, halogen, nitro, cyano group, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, formamyl, sulfamyl, C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl, C 1-4Alkoxyl group, C 1-4Alkyloyl and C 1-4Alkanoyloxy.
5. as the compound of the defined formula of claim 1 (II).
6. the preparation method of claim 5 compound, it comprises the compound of formula (III)
R wherein 4, R 5Such as claim 1 definition, R 6And R 7Such as claim 1 definition, with the compound of formula (IV)
Figure A038236170003C2
Wherein L is a leavings group,
React.
7. the compound of the defined formula of claim 6 (II).
8. the preparation method of claim 7 compound, it comprises the compound of formula V
R wherein 4, R 5And R 7Such as claim 1 definition, with the compound of formula (VI)
R wherein 9And R 10Be alkyl, in the presence of phosphorus oxychloride, react.
9. the preparation method of defined formula (III) compound in the claim 6, it comprises the compound of formula (VII)
Figure A038236170004C2
R wherein 4And R 5Such as claim 1 definition, and R 9And R 10Such as claim 8 definition, with the compound of formula (VIII)
(R 7) 2O
(VIII)
R wherein 7Such as claim 1 definition, react.
10. the compound of the defined formula of claim 9 (VII).
11. preparation as claimed in claim 1 is R wherein 6Be the method for formula (I) compound of hydrogen, comprise that further the compound of resulting formula (I) and the amine of formula (XI) react,
R wherein 14Be selected from hydrogen or C 1-8Alkyl,
M is the integer of 0-4,
Each R 15Be identical or different, and be selected from hydrogen, halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl, C 3-8Cycloalkyl C 1-6Alkyl, aryl, aryl C 1-6Alkyl, heterocyclic radical and (heterocyclic radical) C 1-6Alkyl; R wherein 15On carbon, can choose wantonly by the group of one or more P of being selected from and replace, and if wherein described heterocyclic radical contain one-NH-part, nitrogen can be chosen wantonly by a group that is selected from R and replace so;
Each R 16Be identical or different and be selected from hydrogen and C 1-6Alkyl;
R 17Be selected from hydrogen, halogen, nitro, cyano group, hydroxyl, methyl fluoride, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-4Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, sulfamyl amino, N-(C 1-6Alkyl) sulfamyl amino, N, N-(C 1-6Alkyl) 2Sulfamyl amino, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulfonyl-amino carbonyl, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino and group-E-F-G-H;
Wherein E and G be independently selected from direct key ,-O-,-S-,-SO-,-SO 2-,-OC (O)-,-C (O) O-,-C (O)-,-NR a,-NR aC (O)-,-C (O) NR a,-SO 2NR a-,-NR aSO 2-,-NR aC (O) NR b-,-OC (O) NR a-,-NR aC (O) O-,-NR a-SO 2NR b-,-SO 2NR aC (O)-and-C (O) NR aSO 2-; R wherein aAnd R bSelect hydrogen and the optional C that is replaced by group V independently 1-6Alkyl;
F is the optional C that is replaced by one or more Q 1-6Alkylidene group or direct key;
H is selected from aryl, C 3-8Cycloalkyl and heterocyclic radical; Wherein H can choose wantonly on carbon by the group of one or more S of being selected from and replace, if wherein described heterocyclic radical contains one-NH-part, nitrogen can be chosen wantonly by a group that is selected from T and replace so;
P, S and Q are independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, urea groups, C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 1-6Alkoxyl group, C 1-6Alkyloyl, C 1-6Alkanoyloxy, N-(C 1-6Alkyl) amino, N, N-(C 1-6Alkyl) 2Amino, C 1-6Alkanoylamino, N-(C 1-6Alkyl) formamyl, N, N-(C 1-6Alkyl) 2Formamyl, N-(C 1-6Alkyl)-N-(C 1-6Alkoxyl group) formamyl, C 1-6Alkyl S (O) a, wherein a is 0-2, C 1-6Carbalkoxy, C 1-6Alkoxycarbonyl amino, N-(C 1-6Alkyl) sulfamyl, N, N-(C 1-6Alkyl) 2Sulfamyl, C 1-6Alkyl sulfonyl-amino, C 1-6Alkyl sulphonyl-N-(C 1-6Alkyl) amino, C 3-8Cycloalkyl, aryl and heterocyclic radical; Wherein P, S and Q can be randomly on carbon and are replaced by one or more groups that are selected from V independently, and if described heterocyclic radical contain one-NH-part, nitrogen can be chosen wantonly by a group that is selected from U and replace so;
V is selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino-, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, kharophen, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl-N-ethyl sulfamyl, morpholino, morpholino carbonyl, N-benzylamino formyl radical and 4-hydroxy piperidine subbase carbonyl;
R, T and U are independently selected from C 1-4Alkyl, C 1-4Alkyloyl, C 1-4Alkyl sulphonyl, C 1-4Alkoxy carbonyl, formamyl, N-(C 1-4Alkyl) formamyl, N, N-(C 1-4Alkyl) formamyl, phenyl, benzyl, carbobenzoxy-(Cbz), benzoyl and benzenesulfonyl, wherein R, T and U can randomly and independently be replaced by one or more groups that are selected from V on carbon;
Compound with production (XII)
R wherein 4, R 5, R 15, R 16, R 17With m as defined above, or hydrolyzable ester in its pharmacy acceptable salt or the body.
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